Patch production

ABSTRACT

A method of producing projections on a patch including providing a mask on a substrate and etching the substrate using an etchant and a passivant to thereby control the etching process and form the projections, wherein the passivant does not include oxygen.

BACKGROUND OF THE INVENTION

The present invention relates to a method and apparatus for producingprojections provided on a patch, and in particular to a method andapparatus for producing projections by etching a substrate.

DESCRIPTION OF THE PRIOR ART

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that the prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

It is known to provide patches including a number of projections thereonto allow bioactive material or stimulus to be administered to a subject.Such arrays of projections or needles on a patch are an increasinglyeffective way of delivering stimulus, therapeutic agents or biomarkerssince there is minimal or no pain, little or no injury from the syringeneedle and highly reduced possibility of cross infection.

For example, WO2005/072630 describes devices for delivering bioactivematerials and other stimuli to living cells, methods of manufacture ofthe device and various uses of the device, including a number of medicalapplications. The device comprises a plurality of projections which canpenetrate a body surface so as to deliver the bioactive material orstimulus to the required site. The projections are typically solid andthe delivery end section of the projection is so dimensioned as to becapable of insertion into targeted cells to deliver the bioactivematerial or stimulus without appreciable damage to the targeted cells orspecific sites therein.

In order to function correctly, the projections typically need to have asufficient length to pierce the stratum corneum. Examples of theprojections include sub-millimeter and micron sized needles or bladesthat can be effective in delivering material through the skin.

A number of different techniques have been proposed for forming patchesof needles.

For example, U.S. Pat. Nos. 6,334,856 and 6,503,231 describesmicroneedle devices for transport of therapeutic and biologicalmolecules across tissue barriers. In this process, an appropriatemasking material (e.g., metal) is deposited onto a silicon wafersubstrate and patterned into dots. The wafer is then subjected to plasmabased on fluorine/oxygen chemistries to etch very deep, high aspectratio trenches into the silicon.

U.S. Pat. No. 5,201,992 describes methods for forming tapered siliconstructures, of interest for use in atomic force microscopes, infield-emission devices, and in solid state devices are made usingsilicon processing technology. Resulting tapered structures have, attheir tip, a radius of curvature of 10 nanometers or less. Suchpreferred silicon structures are particularly suited as electronemitters in display devices.

However, the projections produced using fluorine/oxygen based etchingtend to have a concave profile, particularly when applied to projectionshaving a length of less than 500 μm, resulting in a narrow tip, which isthin and liable to breakage. This limits the ability of such projectionsto adequately deliver stimulus or material to a subject, which in turnlimits their effectiveness.

Etching processes tend to lead to a bullseye effect, in which there arevariations in the effectiveness of the etching process across a waferbeing etched. As a result, when a wafer is divided into patches, some ofthe patches are unusable as they are inadequately or over etched. Influorine/oxygen etching process, the bullseye effect tends to lead to ahigh percentage of unusable patches, such as about 40%. This high rateof inefficiency leads to high production costs due to the expense of thewafer material.

Additionally, these prior art techniques typically require a hard maskmaterial such as metal mask, in order to allow the process to beperformed. Such masks are difficult and expensive to obtain and use,thereby further hindering the production of useable patches using theprior art techniques.

U.S. Pat. No. 6,551,849 describes an alternative technique that involvesforming an array of micro-needles by creating an array pattern on theupper surface of a silicon wafer and etching through openings in thepattern to define micro-needle sized cavities having a desired depth, tothereby form a mould. The mould thus formed may be filled withelectrically conductive material, after which a desired fraction of thesilicon wafer bulk is removed from the bottom-up by etching, to exposean array of projecting micro-needles.

However, all of the above described methods also require a significantnumber of processes to manufacture a micro-needle array. This tends tomake the manufacturing process slow and difficult to reproduce withsuitable quality, in high volume and in short time scales, which in turnleads to the production process being extremely expensive, particularlyon a commercial scale.

As a result, recent developments in producing needle patches havefocused on other manufacturing techniques, such as chemical vapourdeposition, dopant diffusion, electron beam machining, wet and dryetching, laser cutting, masking, oxidation, photo-lithography, physicalvapour deposition and scribing.

However, these other techniques are also proving ineffective at massproducing needle patches of suitable physical properties at an economicrate. As a result, the prior methods and devices for the delivery ofmaterial through the skin have exhibited limited success in transferringlaboratory scale investigations to industrial scale production.

SUMMARY OF THE PRESENT INVENTION

The present invention seeks to ameliorate any one or more of thedisadvantages of the prior art.

In a first broad form the present invention provides a method ofproducing projection on a patch, the method including:

-   -   a) providing a mask on a substrate; and,    -   b) etching the substrate using an etchant and a passivant to        thereby control the etching process and form the projections,        wherein the passivant does not include oxygen.

Typically the mask includes an organic photo-resist.

Typically the passivant is a gas including:

-   -   a) at least one of:        -   i) carbon; and,        -   ii) silicon; and,    -   b) at least one of:        -   i) chlorine; and,        -   ii) fluorine.

Typically the passivant is at least one of:

-   -   a) a per-fluoride hydrocarbon; and,    -   b) a fluorinated olefine;    -   c) Octafluorocyclobutane;    -   d) Perfluoroisobutene; and,    -   e) C₄F₈.

Typically the etchant is a gas or plasma.

Typically the etchant is sulphur hexa-fluoride.

Typically the method includes, controlling the etching process byvarying etching parameters including at least one of:

-   -   a) a ratio of the etchant to the passivant;    -   b) a gas flow for at least one of the etchant and the passivant;        and,    -   c) a pressure for at least one of the etchant and the passivant.

Typically the ratio is in the range of 0.25 to 0.60.

Typically the pressure of at least one of the etchant and the passivantis in the range of 0 to 26.7 Pa (0 to 200 mT).

Typically the pressure of at least one of the etchant and the passivantis in the range of 0.67 to 8.0 Pa (5 to 60 mT).

Typically the etchant is supplied at a flow rate in the range of atleast one of:

-   -   a) 0 to 200 sccm; and,    -   b) 40 to 120 sccm.

Typically the passivant is supplied at a flow rate in the range of atleast one of:

-   -   a) 0 to 200 sccm; and,    -   b) 10 to 80 sccm.

Typically the method includes:

-   -   a) applying a mask material to the substrate; and,    -   b) selectively exposing the mask material to radiation to        thereby form the mask.

Typically the mask material is at least one of:

-   -   a) an organic photo-resist;    -   b) a polymer mask; and,    -   c) a crosslinked epoxy resin.

Typically the mask material is Su-8.

Typically the method includes, performing post-etch processing.

Typically the method includes, chemically sharpening the projections.

Typically the method includes, sharpening the projections by:

-   -   a) forming a silicon dioxide layer on the projections; and,    -   b) removing the silicon dioxide layer.

Typically the method includes forming a silicon dioxide layer on theprojections by heating the projections in an oxygen rich environment.

Typically the method includes heating the projections to a temperatureof greater than 1000° C.

Typically the method includes removing the silicon dioxide using 10% HF.

Typically the method includes, applying a coating to the projections.

Typically the coating is a metallic coating.

Typically the method includes using sputter deposition to deposit:

-   -   a) an adhesion layer; and,    -   b) a metallic layer on the adhesion layer.

Typically the adhesion layer includes chromium.

Typically the metal layer includes gold.

Typically the method further includes coating the projections with amaterial.

Typically the material is a therapeutic agent.

Typically the patch has a surface area of approximately 0.4 cm².

Typically the projections have a density of between 1,000-30,000projections/cm².

Typically the projections have a density of 20,000 projections/cm².

Typically the projections have a length of between 10 to 200 μm.

Typically the projections have a length of 90 μm

Typically the projections have a radius of curvature of greater than 1μm.

Typically the projections have a radius of curvature greater than 5 μm.

Typically the projections include a support section and a targetingsection.

Typically the targeting section has a diameter of less than at least oneof:

-   -   a) 1 μm; and,    -   b) 0.5 μm.

Typically a length for the targeting section is at least:

-   -   a) less than 0.5 μm; and,    -   b) less than 1.0 μm; and,    -   c) less than 2.0 μm.

Typically a length for the support section is at least one of:

-   -   a) for epidermal delivery <200 μm;    -   b) for dermal cell delivery <1000 μm;    -   c) for delivery to basal cells in the epithelium of the mucosa        600-800 μm; and,    -   d) for lung delivery of the order of 100 μm in this case.

In a second broad form the present invention provides a method ofproducing projection on a patch, the method including:

-   -   a) providing a mask on a substrate, the mask including an        organic photo-resist material; and,    -   b) etching the substrate using an etchant and a passivant to        thereby control the etching process and form the projections.

In a third broad form the present invention provides a method ofcontrolling an etching process to thereby produce projections on apatch, the method including:

-   -   a) etching the substrate using an etchant; and,    -   b) using a passivant other than oxygen to control the etching.

In a fourth broad form the present invention provides a method ofproducing projection on a patch, the method including:

-   -   a) providing a mask on a substrate; and,    -   b) etching the substrate using an etchant and a passivant to        thereby control the etching process and form the projections,        wherein the passivant includes at least one of:        -   i) a per-fluoride hydrocarbon; and,        -   ii) a fluorinated olefine;        -   iii) Octafluorocyclobutane;        -   iv) Perfluoroisobutene; and,        -   v) C₄F₈.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the present invention will now be described with referenceto the accompanying drawings, in which:

FIGS. 1A and 1B are schematic side and plan views of an example ofdevice for delivery of material to targets within a body;

FIG. 1C is a schematic diagram of an example of the device of FIG. 1A inuse;

FIGS. 1D to 1F are schematic diagrams of examples of projections used inthe device of FIG. 1A;

FIG. 2 is an example of a secondary electron image of a concave profiledprojection;

FIG. 3 is an example of a secondary electron image of a straightprofiled projection;

FIG. 4 is an example of a secondary electron image of a projectionhaving a gold coating;

FIGS. 5A to 5C are schematic diagrams of an example of the steps inetching projections in a substrate;

FIGS. 6A to 6C are examples of secondary electron images of projectionsproduced using different etching times;

FIG. 7 is a graph illustrating an example of the effect of mask dotssize and array pitch on etch depth;

FIGS. 8A to 8C are graphs illustrating examples of the variation invertical etch rates depending on C₄F₈:SF₆ ratios, gas flow rates and gaspressures respectively;

FIG. 9 is a graph illustrating an example of the effect of gas flowrates on projection tip angle;

FIG. 10 is a graph illustrating an example of the effect of systempressure on lateral etch rates;

FIG. 11 is a graph illustrating an example of the effect of systempressure on etch uniformity;

FIG. 12 is a graph illustrating an example of the effect of C₄F₈:SF₆ratio on projection length;

FIGS. 13A to 13C are examples of secondary electron images ofprojections following an O₂ plasma clean; an ultrasonic bath clean; andoxidation and HF sharpening, respectively;

FIGS. 14A to 14C are secondary electron images of example patchesincluding projections having lengths of 60, 100 and 150 μm,respectively; and,

FIG. 14D is a secondary electron image of a projection patch afterinsertion into a subject;

FIGS. 15A and 15B are examples of secondary electron images ofprojections obtained using a high rate Oerlikon etching system;

FIGS. 16A and 16B are examples of secondary electron images ofprojections obtained using a high rate STS etching system;

FIG. 17 is an example of a secondary electron images of projectionsobtained using a lower system pressure and power; FIGS. 18A to 18E aresecondary electron images of examples of projections having a conicalstraight edge profile;

FIGS. 19A and 19B are secondary electron images of examples ofprojections having a conical convex edge profile;

FIGS. 20A to 20E are secondary electron images of examples ofprojections having a stepped profile;

FIG. 21 is a secondary electron image of examples of projections havinga hyper sharp tip;

FIG. 22 is a secondary electron image of examples of projections havinga conical convex edge generated using a ramped etch process;

FIGS. 23A and 23B are secondary electron images of examples ofprojection arrays having coated and uncoated projections respectively;

FIGS. 24A and 24B are examples of CryoSEM images illustrating thepenetration of skin by the projections on a patch;

FIGS. 25A and 25B are examples of CryoSEM images illustrating thepenetration of skin by the projections on a patch;

FIGS. 26A and 26B are secondary electron images of a patch afterapplication to mouse ear skin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An example of a device for delivering material to targets within a bodywill now be described with reference to FIGS. 1A to 1F.

In this example, the device is in the form of patch 100 having a numberof projections 110 provided on a surface 121 of a substrate 120. Theprojections 110 and substrate 120 may be formed from any suitablematerial, but in one example, are formed from a silicon type material.The projections may be solid, non-porous and non-hollow, although thisis not essential.

In the example shown, the patch has a width W and a breadth B with theprojections 110 being separated by spacing S.

In use, the patch 100 is positioned against a surface of a subject,allowing the projections to enter the surface and provide material totargets therein. An example of this is shown in FIG. 1C.

In this example, the patch 100 is urged against a subject's skin showngenerally at 150, so that the projections 110 pierce the Stratum Corneum160, and enter the Viable Epidermis 170 to reach targets of interest,shown generally at 180. However, this is not essential and the patch canbe used to deliver material to any part or region in the subject.

It will be appreciated that the projections can have a variety ofshapes, and examples of suitable projection shapes are shown in moredetail in FIGS. 1D, 1E and 1F.

In one example, the projection includes a targeting section 111,intended to deliver the material or stimulus to targets within the body,and a support section 112 for supporting the targeting section 111.However, this is not essential, and a single element may be used.

In the example of FIG. 1D, the projection is formed from a conicallyshaped member, which tapers gradually along its entire length. In thisexample, the targeting section 111 is therefore defined to be the partof the projection having a diameter of less than d₂.

In FIGS. 1E and 1F, the structure of the projection may vary along itslength to provide a defined targeting section 111 with a designedstructure. In the example of FIG. 1E, the targeting section 111 is inthe form of a substantially cylindrical shape, such that the diameter d₁is approximately equal to the diameter d₂, with a tapered supportsection, such that the diameter d₂ is smaller than the diameter d₃. Incontrast, in the example of FIG. 1F, the targeting section 111 is in theform of taper such that the diameter d₁ is smaller than the diameter d₂,with a cylindrical support section, such that the diameter d₂ issubstantially equal to the diameter d₃.

In general, the support section 112 has a length a, whilst the targetingsection 111 has a length l. The diameter of the tip is indicated by d₁,whilst the diameter of the support section base is given by d₃.

In use, the device can be used to deliver material to specific targetswithin the body or more generally to the blood supply, or tissue withinthe body and the configuration of the device will tend to depend on itsintended use.

Thus, for example, if the patch is configured so as to ensure materialis delivered to specific targets such as cells, then it may be necessaryto select a more specific arrangement of projections than if delivery isprovided more generally to the blood. To achieve this, the device can beprovided with a particular configuration of patch parameters to ensurespecific targeting. The patch parameters can include the number ofprojections N, the spacing S between projections, and the projectionsize and shape. This is described in more detail in co-pendingapplication U.S. Ser. No. 11/496,053.

In one specific example, a patch having a surface area of approximately0.16 cm² has projections provided at a density of between 1,000-30,000projections/cm², and typically at a density of approximately 20,000projections/cm². However, alternative dimensions can be used. Forexample, a patch for an animal such as a mouse may have a surface areaof 0.32 to 0.48 cm², whereas as a patch for a human may have a surfacearea of approximately 1 cm². A variety of surface areas can be achievedby mounting a suitable number and arrangement of patches on a commonsubstrate.

The projections typically have a length of between 10 to 200 μm andtypically 90 μm with a radius of curvature of greater than 1 μm and moretypically greater than 5 μm. However, it will be appreciated that otherdimensions may be used.

If distinct targeting section and support sections are provided, thetargeting section typically has a diameter of less than 1 μm and moretypically less than 0.5 μm. The length of the targeting section istypically less than 100 μm, less than 10 μm and typically less than 5μm. The length of the support section typically varies depending on thelocation of the target within the subject. Example lengths include lessthan 200 μm for epidermal delivery, less than 1000 μm for dermal celldelivery, 600-800 μm for delivery to basal cells in the epithelium ofthe mucosa and approximately 100 μm for lung delivery.

A process for the production of projections on a patch will now bedescribed.

In one example, the process includes providing a mask on a substrate andetching the substrate using an etchant and a passivant to therebycontrol the etching process and form the projections.

The etchant is typically a compound formed from a group 16 element and ahalide. In one example, the etchant contains sulphur and fluorine, andmay therefore include sulphur hex-fluoride (SF₆) or the like.

The passivant is typically a gas other than oxygen, and in particulartypically includes a group 14 element and a halide. In one example, thepassivant is a per-fluoride hydrocarbon such as octafluorocyclobutane(C₄F₈).

The use of suitable etchants and passivants other than oxygen allows fora high degree of control to be provided over the etching process. Inparticular, adjusting etch parameters such as the passivant to etchantratio, the gas flow and the system pressure, this allows etching ratesto be controlled. This in turn allows the degree to which the process isisotropic or anisoptropic to be adjusted. By controlling the relativecharacteristics, this allows the shape of the resulting projections tobe carefully controlled.

The mask may be provided on the substrate using any one of a suitablenumber of techniques. However, in one example, this is achieved byapplying a mask material to the substrate and then selectively exposingthe mask material to radiation to thereby form the mask. When passivantsother than oxygen are used, the mask material can be formed from anorganic photo-resist, such as a crosslinked epoxy resin based polymer.An example of such a material is Su-8 2000 supplied by MicroChem Corp,although other similar related materials can be used. Polymer masks aregenerally significantly easier to create and use, resulting in theprocess being significantly cheaper than when a hard mask, such as ametal mask is used.

Accordingly, the above described technique allows for the production ofsilicon projections to be completed using a combination of opticallithography and deep silicon etching. This allows the profile of theprojections to be carefully controlled, thereby allowing projectionssuitable for use in a range of applications to be created.

Prior art techniques utilising fluorine/oxygen chemistry provide onlyextremely limited control over the etching process. This is in part dueto the formation of a SiliconOxyFluoride layer on the surface of thewafer as part of the passivation process. Formation of the layer occursrapidly and is difficult to control. Furthermore, the hardness of thelayer means that it tends to interfere with the remainder of the etchprocess. As a result, it is generally only possible to produceprojections having a concaved profile, which in turn results in a narrowtip that is thin and liable to breakage. A secondary electron image ofan example of a concave profiled projection is shown in FIG. 2.

In contrast to this, by using a suitable alternative passivant tothereby control the etching process, this avoids the formation of aSiliconOxyFluoride layer, which in turn allows a greater control overprojection shape to be achieved. In one example, this can be used toallow for a more straight profiled conical shape to be produced, anexample of which is shown in FIG. 3. By virtue of the thicker tip shape,this provides for more robust projections which are more capable ofdelivery of material or stimulus to a desired target within a subject.Other shapes can also be provided for, as will be described in moredetail below.

Further benefits are also obtained. In particular, the use of the abovedescribed passivants and etchants, allows an organic based photo-resiststo be used as masks, instead of the metal required by the prior art. Theorganic based photo-resist masks are easier and cheaper to produce.Additionally, these can be of a reduced height as compared to the metalmasks required in fluorine/oxygen based etching processes, which in turnprovides further control over the resulting patch geometry.

In addition to the steps described above, following formation of theprojections, one or more post-etch processing steps may be performed.

In one example, following formation of the projections, the projectionsundergo a chemical sharpening process. Chemical sharpening is performedso as to reduce the roughness of the projections, which can in turnenhance the ability of the projections to deliver material or stimulusto targets within the subject. Sharpening may be achieved in any one ofa number of manners, but in one example, is achieved by forming asilicon dioxide layer on the projections and then subsequently removingthe silicon dioxide layer. This process will be described in more detailbelow.

A further post-etch process that may be performed is to coat theprojections. Any suitable coating may be used, and this can includecoating the projections with a material to be delivered to the subject,as described for example in co-pending application AU-2007907092.Additionally, and/or alternatively, the projection may be coated with ametallic material such as gold. This can assist binding of othermaterial to the projection, and can also improve surface properties toassist in material delivery to the subject. An example of a gold coatedprojection is shown in FIG. 4.

Examples of the process will now be described in more detail withreference to FIGS. 5A to 5C.

In this example, the first step is to produce a plasma etch mask. Toachieve this, a suitable mask material, such as Su-8, which is aphotoreactive polymer, is applied to a substrate 500, which in oneexample is 4 inch, 500 μm thick 100 silicon wafer. The substrate 500 isthen spun at an appropriate speed to distribute polymer in a layer 510over a surface 501 of the substrate 500. The spin speed is selected tocontrol the thickness of the mask layer 510. In one example, to form aprojection having a length in the region of 50-70 μm, the mask layer 510has a thickness in the region of 7-8 μm. It will be appreciated that athicker mask, such as up to 30 μm may be used.

The substrate 500 and mask layer 510 are optionally treated. This may beperformed, for example to remove any excess solvent, which can beachieved by soft baking the substrate 500 and layer 510 for five minutesat 95° C.

Once suitably prepared, the mask layer 510 can be selectively exposedwith radiation 520 to cause the exposed mask material to harden. In oneexample, this is achieved using a suitable photo-mask 530 and radiationsource. Thus, exposure of the Su-8 film can be performed using chromiumon quartz photo-mask and a Carl Suss MA6 mask aligner set to supply 10mJ/second UV light. Typically complete cross-linking of the Su-8 polymeroccurs after 1.8 seconds of exposure for 1 μm of Su-8 thickness,although longer exposure of up to 30 seconds can be used to ensurecomplete cross-linking of mask layers.

The substrate 500 and mask layer 510 may again be optionally treated,for example by baking for one minute at 95° C. This can be used topromote the formation and release of a Lewis Acids which aids thecross-linking process and formation of a straight sidewall profile forthe mask.

The unexposed mask material can be removed using a suitable solvent.Thus, in the above, the uncross-linked Su-8 can be removed by developingin EC solvent (PGMEA) for two minutes. The complete removal ofuncross-linked Su-8 can be confirmed by washing the wafer with IPA. If awhite precipitated is observed (indicating uncompleted development) thewafer is replaced in the EC solvent for further 30 seconds. Developmentis completed until no white precipitated is observed upon washing withIPA. The excess IPA can be removed by blow drying with dry nitrogen gas.

Further treatment may then be performed, such as hard baking of thewafer 500 at 100° C. for five minutes. This can be used to harden andremove residual developer and IPA for the Su-8 mask. At this stage inthe process, the mask layer 510 includes a number of dots 511, as shownin FIG. 5B. The next stage in the process is the formation ofprojections by etching. In one example, this is achieved using plasmaetching, which can be completed on an STS (Surface Technology Systems)ASE (Advanced Silicon Etch) system. In one example, this is achievedusing SF₆ as the etch gas and C₄F₈ as the passivation gas, although asdescribed above, other gases can be used.

Controlled continuous isotropic plasma etch process was complete with aplasma gas mixture of SF₆:C₄F₈ typically in the ratio range of 0.25 to0.60. Vertical, horizontal and projection tip angle can be controlled toprovide required projection profiles. This is achieved by ramping orvarying the plasma gas condition throughout the etch process, bychanging the rate of gas flow, pressure and SF₆:C₄F₈ ratios.

In one example, by performing a continuous etch for approximately 30-60minutes, projection profiles of concave to convex shapes can beachieved, as shown at 550, 551, 552 in FIG. 5C. Example projectionprofiles obtained in performing etching under similar conditions, butfor different time periods are shown in FIGS. 6A to 6C, which show theresult of etching for 40 mins, 45 mins and 50 mins respectively. In thisinstance, the images highlight how the longer etching time results in anarrower taller projection, as would be expected by the increased amountof etching.

A further alternative, etching can be performed in multiple stages toprovide additional control. In one example, a continuous etch isperformed for approximately 30-60 minutes, with a subsequent etch beingperformed for a further 15-30 minutes. This allows a projection 560having a column shaped supporting section 561 and a conical tip 562 tobe produced, as shown in FIG. 5C.

In one example, the profile of the projection can be formed by alteringetching parameters, such as the SF₆:C₄F₈ ratio, pressures, or the like,between the different etch steps.

Additionally, the wafer 500 can be removed from the ASE system, allowingthe wafer and/or passivant to react with the ambient atmosphere. Thiscan alter the effect of the passivant, thereby altering the profilesthat can be produced.

The ability to pause the etching process allows further control over theetching process. For example, the etching can be performed to nearcompletion, with the process then being halted to allow the wafer orpatches to be examined to determine the amount of etching required tocomplete the process. The process can then be resumed and completed.

Pausing the etching process can be performed as the passivant binds onlyrelatively weakly to the silicon surface. Consequently, even when thepassivant has reacted with the ambient air outside the etching system,the passivant can still be removed when etching recommences. Incontrast, in fluorine/oxygen based etching techniques, the passivantbinds strongly to the silicon surface through covalent bonding.Consequently, when the wafer is removed from the etching system an oxidelayer is formed which cannot be controllably etched. This preventsfluorine/oxygen based etching process from being halted or paused toallow examination of the wafer, which in turn limits the degree ofcontrol that can be achieved.

This effect is particularly exacerbated when etching narrow projections,as the etching has a faster effect as the projection narrows, and theetch nears completion. As a result, when etching narrow projectionsusing a fluorine/oxygen based etching approach, over etching oftenoccurs, resulting in projections that are too narrow and hence fragileto use. This renders the resulting patches useless, which in turn leadsto increased manufacturing costs.

The achievable height of the projections is dependent on a number offactors, such as the size and pitch (separation) of mask dots. Anexample of the effect of mask dots size and array pitch on etch depth isshown in FIG. 7. To form projections having a height in the region of 70μm, the dots are typically formed with a diameter in the region of 7-8μm. This is a smaller dot size than is typically required in afluorine/oxygen based plasma etching technique.

Additionally, plasma conditions effect projection profile control suchthat vertical silicon etch rates decrease with increasing C₄F₈:SF₆ratios, lower gas flow rates and low gas pressures as shown in FIGS. 8Ato 8C.

Similarly lateral etch rates are effected, such that by increasingC₄F₈:SF₆ ratios results in a more anisotropic etch. By increasing totalgas flow or system pressure an increased isotropic etch is observed,producing a more concave shaped of projection. The effect of gas flowrates on tip angle is shown in FIG. 9, with the effect of over pressureon lateral etch rates being shown in FIG. 10. FIG. 11 is a graphillustrating an example of the effect of system pressure on etchuniformity. This illustrates that in general a lower pressure of below1.3 Pa (10 mT) is preferred to ensure good etch uniformity.

FIG. 12 is a graph of the effect of C₄F₈:SF₆ ratio on projection lengthfor etching performed using a 50 μm dot 70 μm pitch mask, at 0.3 Pa (2.5mT), total flow rate 100 sccm and power 800 watts. This illustrates thatas the C₄F₈:SF₆ ratio increases, so does the projection length that canbe achieved.

Typically etchant is supplied at a flow rate in the range of 0 to 200sccm (standard centimetre cube per minute), and more typically in therange of 40 to 120 sccm. Passivant may be supplied at a flow rate in therange of 0 to 200 sccm, and more typically in the range of 10 to 80sccm.

Accordingly, by varying etch parameters such as the passivant to etchantratio, the gas flow and the system pressure, this allows projectionheights and profiles to be well defined.

Additionally, by appropriate selection of etch parameters, the bullseyeeffect can be dramatically reduced when compared to fluorine/oxygenetches, thereby increasing the amount of useable patches that can beobtained from a etching process, which in turn increases the costeffectiveness of the process.

In one example, to obtain greater projection lengths, a conventionalswitched BORSH process can be performed. However, this is not essentialand may depend on the system being used to perform the etching process.

Following completion of the etching, the etch mask can be removed andthe silicon wafer chemical cleaned. This can be performed using anoxygen plasma and washing of silicon wafer in micro-strip (concentratedH₂SO₄ peroxide mixture).

Sharpening of the projections can be achieved via the formation of asilicon dioxide layer on the projections by heating the projections inan oxygen rich environment. In one example, a 1-2 μm thick layer ofthermal silicon dioxide is formed by heating at 1050° C. under oxygenfor 24-48 hours. The oxide is subsequently removed using 10% HF andwashing in distilled water.

Examples of the appearance of the projections after cleaning with O₂plasma, after an ultrasonic bath clean and following oxidation and HFsharpening are shown in FIGS. 13A to 13C. These highlight how thecleaning and sharpening process result in smooth projections that areideal for skin penetration.

Further optional treatment can be performed such as baking the wafer at100° C. for 10 minutes to remove residual water.

Following this, gold coating can optionally be preformed using a DCsputter coating system. To achieve this, it is typical to clean thewafer surface using Argon gas sputtering before the depositing 50 nm ofChromium to act as an adhesion layer, followed by 100 nm of Gold.

A further benefit of the provision of a gold coating is to enhance thephysical properties of the projections. Silicon tends to be brittle andas a result can fracture in use due to crack growth. However, the goldprovide a soft ductile coating, which tends to absorb unwanted forcesand impacts, thereby enhancing the resilience of the projections andreducing their failure rate in use.

The final wafer may be further cleaned using Argon gas sputtering.

Examples of patches including 60, 100 and 150 μm length projections areshown in FIGS. 14A to 14C. An example of a projection patch afterinsertion into a subject is shown in FIG. 14D. It can be seen that theprojections remain unbroken, highlighting that the projections arestrong enough to remain intact after insertion into the subject.

The use of the processes described above can provide any one or more ofa number of advantages.

For example, the use of a suitable passivation gas such as C₄F₈ allowsthe direct use of an organic photo-resist (for example Su-8). Su-8 is ahigh aspect ratio negative resist with good plasma etching properties(i.e. selectivity). A greatly increased selectivity of mask to siliconetching is found when using a passivant other than oxygen, such as C₄F₈.This allows for a simplification in manufacturing by reducing the numberof process steps. Firstly the need for deposition of a hard etch mask isremoved (no deposition of metals or dielectric required), secondlyetching of the hard mask not required and thirdly removal photo-resistnot necessary.

Su-8 is suitable for use in both anisotropic and isotropic etching.Using Su-8 as an etch mask provides a considerable reducing inproduction costs and time compared to prior art processes.

Using a passivation gas such as C₄F₈ allows a greater control overprojection tip profiles to be provided. The use of oxygen as apassivation, gas unless employed in a cryo ICP system, will produce aconcave profile. However, cryo ICP systems are generally expensive tooperate and maintain, thereby making this technique unsuitable for useon a mass scale. Using C₄F₈ as a passivation gas, projections withprofiles of concave, flat and convex form can be produced. The use ofparameter ramping allows a high degree of tip profile control to bemaintained.

Additionally, etching can be paused, allowing additional control overthe etching process. This can be used to allow a range of differentprojection profiles to be produced, as well as to control termination ofthe etching process more accurately.

The use of fluorocarbons, such as C₄F₈ also reduces the impact of thebullseye effect, thereby increasing the amount of useable patchesresulting from the etching process.

Chemical sharpening and surface morphology changes to silicon projectiontips. Chemical sharpening to <10 nm tip diameter can be achieved,allowing for easier penetration of the stratum corneum with lesspressure being required.

Wet and dry oxidation sharpening methods can be used. Morphologicaldifferences have been observed between wet and dry oxidation conditionsconsequently smooth or porous surface structure can be producedrespectively. Porosity can also be further increased usingelectrochemical methods.

Gold can be used as an adhesion layer for delivery of DNA and biologicalmaterials with using the projections. This can also enhance the physicalproperties of the projections, thereby reducing their failure rate.

Accordingly, the above described process provides for the more efficientand cost effective manufacture of projections by plasma etching, as wellas enabling greater control over the etching process, to allow specificprojection profiles to be created.

A number of example projection shapes are shown in FIGS. 15A, 15B, 16A,and 16B.

In the examples of FIGS. 15A and 15B, etching is performed as a two stepprocess, using a SF₆:C₄F₈ ratio 2.5 for the first step and a SF₆:C₄F₈ratio 1.2 for the second step. Both steps are performed at 2000 watts,200 sccm total gas flow and 26.6 Pa (200 mT) pressure, using an Oerlikonetching system, which typically can etch at higher rates that the STSASE system discussed above. In these examples a grainy structure ispresent at the top of the projections due to excess HF in the chamber.

FIGS. 16A and 16B show similar results are obtained for a high rate STSetch. In this example, the projections have a length of 120 μm. Thecreation of a grainy structure can be reduced either by using a lowersystem power and pressure, which results in the smooth shapedprojections shown in FIG. 17. However, in this example, the reducedpressure and power results in a shorter projection having a length of 80μm, for similar etching parameters.

Example patch configuration produced using the above described etchingtechniques will now be described with reference to FIGS. 18 to 22.

In the example of FIGS. 18A and 18E, a single stage etching process isused to produce projections having a conical shape.

For the example of FIGS. 18A and 18B, the etching parameters are broadlyas set out below, resulting in projections having a length ofapproximately 50-70 μm depth, sub-micron sharp, 3-to-1 base to lengthaspect ratio, with a straight edge profile:

-   -   Etch mask 30 μm dot with 70 μm pitch;    -   Resist: Su8-5 spun to give 10 μm thickness    -   Etch: 36 sccm C₄F₈ passivant, 64 sccm SF₆ etchant,        -   pressure 0.3 Pa (2.5 mT),        -   power 800 watts coil, 20 watts platen        -   time 50 minutes.

A similar single stage etching process can be used with differentetching parameters to produce projections have dimensions of 30 μmlength, 70 μm spacing; 50 μm length, 70 μm spacing; and 70 μm length,100 μm spacing, as shown in FIGS. 18C to 18E, respectively. It will beappreciated from this that a range of different conical projections canbe produced and that these are for the purpose of example only.

In the example of FIGS. 19A and 19B, a single stage etching process isused to produce projections having a conical shape, with a convexprofile edge. In this example, using the etching parameters set outbelow, the projections typically have a length of approximately 150 μm,sub-micron sharp, 5-to-1 base to length aspect ratio, with a convexprofile:

-   -   Etch mask 50 μm dot with 70 μm pitch    -   Resist: Su8-25 spun to give 25 μm thickness    -   Etch: gases 37 sccm C₄F₈passivant, 63 sccm SF₆ etchant,        -   pressure 0.3 Pa (2.5 mT),        -   power 800 watts coil, 20 watts platen        -   time 2 hours 15 minutes

In the examples of FIGS. 20A to 20E, a two stage etching process is usedto produce stepped projections having a cylindrical base and conicalshaped tip.

For the example of FIGS. 20A and 20B, the etching parameters are broadlyas set out below, resulting in projections having a length ofapproximately 150 μm depth, hyper sharp, 5-to-1 base to length aspectratio:

-   -   Etch mask 30 μm dot with 70 μm pitch    -   Resist: Su8-5 spun to give 10 μm thickness    -   Etch: gases 36 sccm C₄F₈ passivant, 64 sccm SF₆ etchant,        -   pressure 0.3 Pa (2.5 mT),        -   power 800 watts coil, 20 watts platen        -   time 50 minutes        -   1 hour conventional ASE switched etch

In the examples of FIGS. 20C to 20E, alternative parameters are used toproduce projections having lengths of 80 μm, 110 μm, and 65 μmrespectively.

For the example of FIG. 21, the etching parameters are broadly as setout below, resulting in projections having a length of approximately80-90 μm depth, hyper sharp, 5-to-1 base to length aspect ratio:

-   -   Etch mask 30 μm dot with 70 μm pitch    -   Resist: Su8-5 spun to give 15 μm thickness    -   Etch: gases 38 sccm C₄F₈ passivant, 62 sccm SF₆ etchant,        -   pressure 0.3 Pa (2.5 mT),        -   power 800 watts coil, 20 watts platen        -   time 90 minutes

For the example of FIG. 22, the etching parameters are broadly as setout below. In this instance, a ramped etch is performed to result in aconvex edge profile on projections having a length of approximately60-70 μm:

-   -   Etch mask 30 μm dot with 70 μm pitch    -   Resist: Su8-5 spun to give 15 μm thickness    -   Etch: gases 50-80 sccm C₄F₈ passivant, 120 sccm SF₆ etchant,        -   pressure 0.3 Pa (2.5 mT),        -   power 800 watts coil, 20 watts platen        -   time 60 minutes—C₄F₈ gas ramped 0.5 sccm per minute

It will be appreciated that the example etching parameters describedabove are for the purpose of example only and are not intended to belimiting. For example, the parameters will typically be etching systemspecific, so that if similar dimensioned projections are to be producedusing different etching equipment, appropriate modification of theparameters will be required.

Example experiments used to demonstrate the effectiveness of theprojections at delivering material to subjects will now be described.

The tissue used in this experiment was mouse ear skin from 7 week oldC57 Black6 female mice. Experimentation was performed in-vivo followinginjection of Ketamil-Xylasil anaesthetic (Troy laboratories Pty., Ltd.,Smithfield, Australia), in accordance with Australian Animal Ethicsguidelines. In-vivo tests ensured that blood flow was maintained to theskin to highlight erythema and blood vessel damage resulting fromapplication. Five ears (n=5) were used per group in dye delivery andCryo-SEM experiments.

The projection patches used for this study were designed to give a highprobability of Langerhans cell-antigen interaction. The patches arefabricated using the etching techniques outlined above in a two stepprocess, to thereby produce projections having a stepped configurationincluding a conical tip and cylindrical base. In this example, theprojections have a length of 65 μm and a 50 μm conical section, atop a15 μm cylindrical base. The projections have a density of 20,000/cm²,with 4 mm×4 mm projection area on a 5 mm×5 mm silicon base.

The delivery system for this experiment is a solid coating on thesurface of the projections. This coating dissolves once wetted in theskin for the vaccine delivery. These studies were designed to emulatevaccine delivery. 8 μL solution of 0.4% Vybrant® DiD (a lipophilicfluorescent dye, Molecular Probes Inc., Eugene, Oreg.) and 1.5%Methylcellulose was coated on the array using a nitrogen jet methoddescribed in copending application number PCT/AU2008/001903. The dye isused to provide projection penetration tracks when the dye is releasedfrom the projections. Concentrations in solution were titrated forminimal diffusion following insertion.

Examples of coated and uncoated patches are shown in FIGS. 23A and 23B.

After patch application, the skin is prepared for confocal section dyemeasurement. To do this the skin is fixed in 2% Paraformaldehyde in 0.1M Phosphate buffer, preceding cryo-preservation. Once frozen, 10 μmthick sections of skin were cut on a cryostat before imaging on a ZeissLSM510 Meta confocal Multi-Photon Microscope (Carl Zeiss, Inc.,Germany). Dye delivery highlighting projection tracks were measured inlength from the point where the stratum corneum was breached at the edgeof the hole, to the lowest dye point in the skin. An example of thesections used are shown in FIGS. 24A and 24B. Projection holes withsignificant stratum corneum deflection, obscuring the viable epidermis,were neglected as they represent incomplete penetration.

Surface data from microscopy allows information regarding projectionpenetration to be determined. This was done using a Scanning ElectronMicroscope (SEM) fitted with a cryo-stage and preparation chamber(Oxford CT-1500 and Philips XL30 SEM, Philips, Netherlands). For thesestudies the patches were coated as before, before application to theskin. The patch was applied to the skin in the same manner as in the dyestudies. The patch and skin assembly was then slush frozen in liquidnitrogen (LN₂) and transferred to a cryo-preservation chamber undervacuum. At this point the patch was removed from the skin and the skinthen sputter coated with a thin (few nanometers) layer of gold forimaging purposes. This technique ensures that the holes in the surfaceof the skin are as they would be in-situ. Skin morphology changes arerestricted by the projections during the freezing, allowing accuratequantification. Imaging is then performed by SEM.

Application of an MNP patch to skin results in penetrative channelsthrough the stratum corneum to lower layers of the skin, as shown inFIGS. 25A and 25B, in which significant holes are created over almostthe complete 4 mm×4 mm area of the patch.

Using this technique the surface profile is clear, with individualcorneocytes distinguishable. The location of the micro-channels withrespect to the corneocytes (between or through) was seen to have noeffect on penetration. The surface data also shows that areas with hairare punctured similarly to those without, indicating that theprojections are not affected by hairs, simply puncturing through oradjacent to them.

The Cryo-SEM data also allows examination of the patch post-applicationwhere it is removed and an upper layer of corneocytes has remained onthe projections. FIG. 26A shows the entire patch after application tomouse ear skin, whilst FIG. 26B shows a close-up of nine projections.The images show that the patch has large areas covered by corneocyteswhich have been frozen with liquid nitrogen showing their profiles. Thefrozen corneocytes reveal penetration profiles and show the bulkbehaviour of the outermost layer of skin. It is clear that for the caseshown , the step in conical projection geometry is acting to restrainentrance to the skin. This is also evident in the FIG. 18C where thereare circular impressions around projection holes at higher velocitiesindicative of the step reaching the skin. Projection progression appearsto have been restricted by this.

The quantitative measurement of penetration performance of our MNP patchis from raw data such as the typical histological section shown in FIGS.24A and 24B. This shows a section of mouse ear skin and thecorresponding dye delivered. This can be used to measure delivery depthof dye payload, showing successful delivery beyond the stratum corneum.These data show that this device is capable of delivering molecules intothe skin.

It is noticeable that the greatest penetration for these projections isapproximately 65% of their conical length, which corresponds to thelocation at which skin reaches the step in geometry. In particular, whenthe cylindrical portion of the projections reach the surface of the skinthey present a larger cross-sectional area to the corneocytes that theyare touching, allowing the patch to be decelerated and penetrationstopped. This is highlighted by viewing the treated area of skin after a1.96 m/s application, where clear circular impressions around theprojection holes are visible as shown in FIG. 25B.

Accordingly, it will be appreciated that the ability to perform a twostep etch, and hence produce a stepped projection profile, allows thedepth of projection penetration to be controlled in use, which can inturn be used to deliver payloads to specific cells or layers of cells inthe skin. For example, in the case of vaccines, the viable epidermis,and Langerhans cells therein can be targeted directly using a steppedprojection profile of appropriate length.

A number of further variations and options for use with the abovedescribed devices will now be described.

Herein, the terms “projection”, “micro-nanoprojection”, “nanoneedle”,“nanoprojection”, “needle”, “rod” etc are used interchangeably todescribe the projections.

The projections may be used for delivery not only through the skin butthrough other body surfaces, including mucosal surfaces, to cellularsites below the outer layer or layers of such surfaces.

The device is suitable for intracellular delivery. The device issuitable for delivery to specific organelles within cells. Examples oforganelles to which the device can be applied include a cell nucleus, orendoplasmic reticulum, for example.

In one example the device is provided having a needle support section,that is to say the projections comprise a suitable support section, ofsufficient length to reach the desired site and a (needle) delivery endsection having a length no greater than 20 microns and a maximum widthno greater than 5 microns, preferably no greater than 2 microns.

In one example, the maximum width of the delivery end section is nogreater than 1000 nm, even more preferably the maximum width of thedelivery end section is no greater than 500 nm.

In a further example, the device is for mucosal delivery. This devicemay have a needle support section, that is to say the projectionscomprise a suitable support section, of sufficient length to reach thedesired site, such as of length at least 100 microns and a (needle)delivery end section having a length no greater than 20 microns and amaximum width no greater than 5 microns, preferably no greater than 2microns.

In one example, the device of the invention is for delivery to lung,eye, cornea, sclera or other internal organ or tissue. In a furtherexample, the device is for in-vitro delivery to tissue, cell cultures,cell lines, organs, artificial tissues and tissue engineered products.This device typically has a needle support section, that is to say theprojections comprise a suitable support section, of length at least 5microns and a needle delivery end section having a length no greaterthan 20 microns and a maximum width no greater than 5 microns,preferably no greater than 2 microns.

In one example, the device comprises projections in which the (needle)delivery end section and support length, that is to say the “needlesupport section”, is coated with a bioactive material across the wholeor part of its length, as described in further detail in the copendingapplication AU-2007907092. The (needle) delivery end section and supportlength may be coated on selective areas thereof. This may depend uponthe bioactive material being used or the target selected for example.

In a further example, a bioactive material is releasably incorporatedinto the material of which the needle, or projection, is composed. All,or part of the projection may be constructed of a biocompatible,biodegradable polymer (such as Poly Lactic Acid (PLA), PolyGlycolic Acid(PGA) or PGLA or Poly Glucleic Acid), which is formulated with thebioactive material of choice. The projections may then be inserted intothe appropriate target site and, as they dissolve, the bioactivematerial will enter the organelle(s)/cells.

In one aspect, the device is provided in the form of a patch containinga plurality of needles (projections) for application to a body surface.A multiplicity of projections can allow multiple cells and organelles tobe targeted and provided with a material at the same time. The patch maybe of any suitable shape, such as square or round for example. Theoverall number of projections per patch depends upon the particularapplication in which the device is to be used. Preferably, the patch hasat least 10 needles per mm, and more preferably at least 100 needles permm². Considerations and specific examples of such a patch are providedin more detail below.

As an alternative to a gold coating, any suitable biocompatible materialmay be provided as a coating, such as Titanium, Silver, Silicon, or thelike. This may be the entire device, or alternatively it may only be theprojections or the delivery end section of the projections which aremade from the biocompatible materials.

An alternative means for producing masks is with 2 photonStereolithography, a technique which is known in the art and isdescribed in more detail below.

The device may be for a single use or may be used and then recoated withthe same or a different bioactive material or other stimulus, forexample.

In one example, the device comprises projections which are of differinglengths and/or diameters (or thicknesses depending on the shape of theprojections) to allow targeting of different targets within the same useof the device.

Persons skilled in the art will appreciate that numerous variations andmodifications will become apparent. All such variations andmodifications which become apparent to persons skilled in the art,should be considered to fall within the spirit and scope that theinvention broadly appearing before described.

The invention claimed is:
 1. A method of producing projections on apatch, the method including: a) providing a mask on a substrate; and, b)etching the substrate using a mixture of an etchant and a passivant tothereby control the etching process and form the projections, whereinthe etching process is controlled by varying a ratio of the etchant tothe passivant in the mixture, wherein the ratio is in the range of 0.25to 0.60, and wherein the passivant does not include oxygen.
 2. A methodaccording to claim 1, wherein the mask includes an organic photo-resist.3. A method according to claim 1, wherein the passivant is a gasincluding: a) at least one of: i) carbon; and, ii) silicon; and, b) atleast one of: i) chlorine; and, ii) fluorine.
 4. A method according toclaim 1, wherein the passivant is at least one of: a) a per-fluoridehydrocarbon; b) a fluorinated olefine; c) Octafluorocyclobutane; d)Perfluoroisobutene; and, e) C₄F₈.
 5. A method according to claim 1,wherein the etchant is a gas or plasma.
 6. A method according to claim1, wherein the etchant is sulfur hexa-fluoride.
 7. A method according toclaim 1, wherein the method includes, controlling the etching process byvarying etching parameters including at least one of: a) a gas flow forat least one of the etchant and the passivant; and, b) a pressure for atleast one of the etchant and the passivant.
 8. A method according toclaim 7, wherein the pressure of at least one of the etchant and thepassivant is in the range of 0 to 26.7 Pa.
 9. A method according toclaim 7, wherein the pressure of at least one of the etchant and thepassivant is in the range of 0.67 to 8.0 Pa.
 10. A method according toclaim 7, wherein the etchant is supplied at a flow rate in the range of0 to 200 sccm.
 11. A method according to claim 1, wherein the passivantis supplied at a flow rate in the range of 0 to 200 sccm.
 12. A methodaccording to claim 1, wherein the method includes: a) applying a maskmaterial to the substrate; and, b) selectively exposing the maskmaterial to radiation to thereby form the mask.
 13. A method accordingto claim 12, wherein the mask material is at least one of: a) an organicphoto-resist; b) a polymer mask; and, c) a crosslinked epoxy resin. 14.A method according to claim 12, wherein the mask material is Su-8.
 15. Amethod according to claim 1, wherein the method includes, performingpost-etch processing.
 16. A method according to claim 15, wherein themethod includes, chemically sharpening the projections.
 17. A methodaccording to claim 15, wherein the method includes, sharpening theprojections by: a) forming a silicon dioxide layer on the projections;and, b) removing the silicon dioxide layer.
 18. A method according toclaim 17, wherein the method includes forming a silicon dioxide layer onthe projections by heating the projections in an oxygen richenvironment.
 19. A method according to claim 18, wherein the methodincludes heating the projections to a temperature of greater than 1000°C.
 20. A method according to claim 17, wherein the method includesremoving the silicon dioxide using 10% HF.
 21. A method according toclaim 1, wherein the method includes, applying a coating to theprojections.
 22. A method according to claim 21, wherein the coating isa metallic coating.
 23. A method according to claim 21, wherein themethod includes using sputter deposition to deposit: a) an adhesionlayer; and, b) a metallic layer on the adhesion layer.
 24. A methodaccording to claim 23, wherein the adhesion layer includes chromium. 25.A method according to claim 22, wherein the metallic coating includesgold.
 26. A method according to claim 1, wherein the method furtherincludes coating the projections with a material.
 27. A method accordingto claim 26, wherein the material is a therapeutic agent.
 28. A methodaccording to claim 1, wherein the patch has a surface area ofapproximately 0.4 cm².
 29. A method according to claim 1, wherein theprojections have a density of between 1,000-30,000 projections/cm². 30.A method according to claim 1, wherein the projections have a density of20,000 projections/cm².
 31. A method according to claim 1, wherein theprojections have a length of between 10 to 200 μm.
 32. A methodaccording to claim 1, wherein the projections have a length of 90 μm.33. A method according to claim 1, wherein the projections have a radiusof curvature of greater than 1 μm.
 34. A method according to claim 1,wherein the projections have a radius of curvature greater than 5 μm.35. A method according to claim 1, wherein the projections include asupport section and a targeting section.
 36. A method according to claim35, wherein the targeting section has a diameter of less than 1 μm. 37.A method according to claim 35, wherein a length for the targetingsection is less than 2.0 μm.
 38. A method according to claim 35, whereina length for the support section is at least one of: a) for epidermaldelivery <200 μm; b) for dermal cell delivery <1000 μm; c) for deliveryto basal cells in the epithelium of the mucosa 600-800 μm; and, d) forlung delivery of the order of 100 μm an in this case.